Cancer kills hundreds of thousands of people every year in the United States alone, and many more cases of cancer are diagnosed each year. Despite advances in the treatment of certain forms of cancer (including surgery, radiotherapy, and chemotherapy), many types of cancer are essentially incurable. Even when an effective treatment is available for a certain cancer, the side effects of such treatment are often severe and can result in a significant decrease in quality of life.
While there are many forms of cancer, all cancers are characterized by inappropriate cell proliferation. Multiple checkpoints are built into the machinery of the cell proliferation cycle where cells make a commitment to repair DNA damage or to undergo cell death. Unlike normal cells, cancer cells have lost checkpoint control and have an uncontrolled proliferation drive. The approximately 1016 cell multiplications in the human lifetime, together with inevitable errors in DNA replication and exposure to ultraviolet rays and mutagens, underscores the requirement for checkpoint functions. Major checkpoints occur at G1/S phase and at the G2/M phase transitions where cells make a commitment to repair DNA or undergo apoptosis. Cells are generally thought to undergo apoptosis when DNA damage is irreparable (Li, C J et al. (1999) Proc. Natl. Acad. Sci. USA 96:13369-13374).
Identification of therapeutic agents modulating the checkpoint control may improve cancer treatment. Indeed, recent reports suggest that activation of cell cycle checkpoints may represent an important new paradigm in the treatment of cancer (see, e.g., Y. Li et al., Proc. Natl. Acad. Sci. USA (2003), 100(5), 2674-8). The cell cycle checkpoint activator β-lapachone, which acts at the G1/S phase transition, has been found to exhibit significant anti-tumor activity against a range of tumor types both in vitro and in animal studies while exhibiting a favorable side effect profile, leading to the initiation of human clinical trials. In addition, it has been reported that β-lapachone induces necrosis in human breast cancer cells, and apoptosis in ovary, colon, and pancreatic cancer cells through induction of caspase (Li, Y Z et al., (1999) Molecular Medicine 5:232-239).
It has also been reported that β-lapachone, when combined with Taxol® (paclitaxel; Bristol-Myers Squibb Co., N.Y., N.Y.) at moderate doses, has effective anti-tumor activity in human ovarian, prostate and breast cancer xenograft models in nude mice. No signs of toxicity to the mice were observed, and no weight loss was recorded during the subsequent two months following treatment during which the tumors did not reappear (See Li, C J et al. (1999) Proc. Natl. Acad. Sci. USA 96:13369-13374). Taxol is believed to act at the G2/M phase transition of the cell cycle.
Many conventional chemotherapy agents cause damage to cancerous and non-cancerous cells alike. While this broad-spectrum activity allows the chemotherapy to kill many different types of cancers, it often also results in damage to normal cells. The therapeutic index of such compounds (a measure of the ability of the therapy to discriminate between normal and cancerous cells) can be quite low; frequently, a dose of a chemotherapy drug that is effective to kill cancer cells will also kill normal cells, especially those normal cells (such as epithelial cells) which undergo frequent cell division. When normal cells are affected by the therapy, side effects such as hair loss, suppression of hematopoesis, and nausea can occur.
Recent advances in cancer chemotherapeutics have resulted in the development of new “targeted” anti-cancer agents, designed to affect biological targets that are primarily associated with cancerous cells, rather than normal cells. Examples of such agents include imatinib (sold by Novartis under the trade name Gleevec in the United States), gefitinib (developed by Astra Zeneca under the trade name Iressa), and erlotinib (being developed under the name of Tarceva by Genentech, OSI, and Roche). While such agents can be quite effective against the intended cellular target, and can have lower rates of side effects than conventional chemotherapies, targeted therapies are, by design, effective only against cells expressing the biological target. Cancer cells which do not express this specific target, or which express a mutated form of the target, may be less affected by a targeted agent. These agents are therefore of limited utility.
Despite the progress made to date in discovering new anti-tumor treatments, new treatments for cancer are needed.
Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR) which possesses tyrosine kinase activity is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as a selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase but is without effect on the growth of another carcinoma which does not express the EGF receptor.